Lipid Disorder-2

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Peter C. Chien, MD & William H. Frishman, MD

Treatment

A. RATIONALE FOR TREATMENT

The rationale of treatment of hyperlipidemia is based on the hypothesis that abnormalities in lipid and lipoprotein levels are risk factors for CAD and that changes in blood lipids can decrease the risk of disease and complications. Levels of plasma cholesterol and LDL have consistently been shown to directly correlate with the risk of CAD. Since the promulgation of the previous NCEP (Adult Treatment Panel II) guidelines, the results of numerous studies involving the primary and secondary prevention of CAD with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported. These trials have overwhelmingly demonstrated a significant reduction in CAD events, CAD mortality, and mortality from all other causes, in addition to ameliorating LDL-C, HDL-C, and triglyceride levels. Data from the West of Scotland Coronary Prevention Study and from the Air Force/Texas Coronary Atherosclerosis Prevention Study have provided cogent evidence that primary prevention of CAD in hypercholesterolemic individuals reduces the incidence of coronary events and, in the former study, death from cardiovascular events. Secondary prevention trials such as the Scandinavian Simvastatin Survival Study (4S) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study have revealed that lowering LDL cholesterol levels can retard the progression of coronary atherosclerosis and reduce CAD events, CAD mortality, and cerebrovascular events. These compelling data have prompted a more aggressive approach to the treatment of hyperlipidemia, culminating in the new NCEP (Adult Treatment Panel III [ATP III]) guidelines (Table 2–4). Although ATP III maintains attention to intensive treatment of patients with CAD, its major new focus is on primary prevention in patients with multiple risk factors (Table 2–5).

Table 2–4. ATP III classification of LDL, total and HDL cholesterol (mg/dL).

Table 2–5. New features of ATP III.

Epidemiologic studies and clinical trials are consistent in supporting the observation that for individuals with serum cholesterol levels in the 6.47–7.76 mm/L (250–300 mg/dL) range, each l% reduction in serum cholesterol would yield about a 2% reduction in the rate of combined morbidity and mortality from coronary heart disease. The absolute magnitude of these benefits would even be greater in those individuals having other risk factors for CAD, such as cigarette smoking and hypertension. These risk relationships are the basis for recommending lower cholesterol cutpoints and goals for those who are at high risk for developing coronary heart disease.
Recent meta-analyses have indicated that triglycerides are an independent risk factor for the development of CAD. In addition, serum triglyceride levels are inversely related to HDL levels, and a reduction in triglyceride levels is associated with a rise in HDL. Raising HDL may protect against CAD, therefore providing an additional rationale for treating hypertriglyceridemia.
Downs JR, Clearfield M, Weis S et al: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615.
The Long-Term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary artery disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1357.
Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383.
Shepherd J, Cobbe SM, Ford I et al: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301.
B. TREATMENT GUIDELINES

1. Hypercholesterolemia—The NCEP has classified all adult patients into those with desirable cholesterol values (5.17 mm/L [<200 mg/dL]), borderline high blood cholesterol values (5.17–6.l8 mm/L [200–239 mg/dL]), and high blood cholesterol values (6.21 mm/L [³240 mg/dL]) (see Table 2–4). LDL-C values of <2.58 mm/L (l00 mg/dL) are considered optimal; those between 2.58 and 3.36 mm/L (100–129 mg/dL) are near optimal; those between 3.36 and 4.11 mm/L (130–159 mg/dL) are borderline high; those between 4.13 and 4.88 mm/L (160–189 mg/dL) are high; and those greater than or equal to 4.91 mm/L (190 mg/dL) are very high. HDL-C values of less than 1.03 mm/L (40 mg/dL) are considered to be low, and those greater than or equal to 1.54 mm/L (60 mg/dL) are considered to be high.
The NCEP recommends an approach in adults based on LDL-cholesterol levels (Figure 2–2, Table 2–6). Management should always begin with dietary intervention, as outlined in Table 2–7. When response to diet is inadequate, the NCEP recommends the addition of pharmacologic therapy (Figure 2–3).

Figure 2–2. Model of steps in therapeutic lifestyle changes (TLC). Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2491 (Fig. 1).

Figure 2–3. Progression of drug therapy in primary prevention. Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2492 (Fig. 2).

Table 2–6. LDL cholesterol goals and cutpoints for therapeutic lifestyle changes (TLC) and drug therapy in different risk categories.

Table 2–7. Nutrient composition of the therapeutic lifestyle changes (TLC) diet.

2. Hypertriglyceridemia—Non-HDL cholesterol, comprising LDL and VLDL, is a secondary treatment goal in patients with hypertriglyceridemia (levels > 200 mg/dL). The non-HDL cholesterol goal is set at 30 mg/dL higher than the LDL target level. Triglyceride values of less than 1.69 mm/L (150 mg/dL) are regarded as optimal; those from 1.69 to 2.25 mm/L (150–199 mg/dL) are borderline high; those from 2.26 to 5.64 mm/L (200–499 mg/dL) are high; and values greater than or equal to 5.65 mm/L (500 mg/dL) are considered to be very high. A link between plasma triglycerides and disease is most apparent in patients with severe hypertriglyceridemia with chylomicronemia. These patients are prone to abdominal pain and pancreatitis. Both changes in lifestyle (control of weight, increased physical activity, restriction of alcohol, restriction of dietary fat to 10–20% of total caloric intake, reduction of high carbohydrate intake) and drug therapy are often required.
Much of hypertriglyceridemia (2.82–5.65 mm/L [250–500 mg/dL]) is due to various exogenous or secondary factors (see Table 2–2), which include alcohol, diabetes mellitus, hypothyroidism, obesity, chronic renal disease, and drugs. Changes in lifestyle or treatment of the primary disease process may be sufficient to reduce triglyceride levels.
Patients with high triglycerides that is familial in origin (type IV) are not at risk for premature CAD. Caloric restriction and increased exercise should be instituted as first-line therapies. Patients with familial combined hyperlipoproteinemia often have mild hypertriglyceridemia and are at risk of premature coronary heart disease. These patients should have dietary treatment first, followed, if necessary, by drugs. Patients with high triglycerides and clinical manifestations of CAD can be treated as though they have familial combined hyperlipoproteinemia.
3. Low serum HDL cholesterol—A low serum HDL cholesterol level has emerged as the strongest single lipoprotein predictor of coronary heart disease. Although clinical trials suggest that raising HDL will reduce the risk of CAD, the evidence is insufficient at this time to specify the goal of therapy. The major causes of reduced serum HDL-C are shown in Table 2–8. Clearly, attempts should be made to raise low HDL-C by nonpharmacologic means. When a low HDL is associated with an increased VLDL, therapeutic modification of the latter should be considered, but attempts to raise HDL levels by drugs when there are no other associated risk factors cannot be justified.

Table 2–8. Major causes of reduced serum HDL-cholesterol.


4. Coronary artery disease—
a. Myocardial infarction—Numerous trials have demonstrated the efficacy of employing HMG-CoA reductase inhibitors in the primary and secondary prevention of CAD. Lipid-lowering agents especially benefit hypercholesterolemic patients at the greatest risk for coronary events—those with CAD and CAD equivalents, such as diabetes mellitus, symptomatic cerebrovascular disease, abdominal aortic aneurysm, and peripheral vascular disease. The NCEP now classifies these conditions as tantamount to having established CAD because of their high prevalence of overt and subclinical atherosclerosis. The goal LDL for CAD and its equivalents is less than 2.6 mm/L (100 mg/dL), and dietary modification should be implemented in patients exceeding this target level, with concurrent initiation of drug therapy also being a consideration. Patients should obtain a fasting lipid profile within 24 h of the onset of an acute coronary syndrome or several weeks after the event because LDL levels may remain depressed and yield spurious results. It is recommended that drug therapy be initiated whenever a patient is hospitalized and found to have an LDL-C above 100 mg/dL.
b. Coronary artery bypass grafts—Progressive atherosclerosis has been identified as the single most important cause of occlusion of saphenous vein coronary artery grafts; it is found in approximately two thirds of grafts within 10 years. Low HDL-C, high LDL-C, and high apolipoprotein B are the most significant predictors of atherosclerotic disease in grafts. Many investigators believe that internal mammary artery bypass grafting is the coronary bypass procedure of choice because atherosclerosis progresses less rapidly with these grafts than with saphenous veins. Moreover, lipid-lowering therapy may improve the patency of bypass grafts. The Coronary Artery Bypass Graft Trial demonstrated that aggressive LDL reduction as compared to moderate LDL reduction attenuated the progression of atherosclerosis in saphenous vein coronary artery bypass grafts. It also concluded that low-dose warfarin was ineffective in achieving this end-point.
c. Coronary angioplasty—Restenosis after successful coronary angioplasty has been observed in 25–40% of patients undergoing this procedure. Restenosis after angioplasty appears to result from intimal smooth muscle cell proliferation. Placement of coronary stents has reduced angioplasty restenosis rates, CAD events, and the need for repeat revascularization procedures. Stent patency may be improved with the subsequent administration of glycoprotein IIb/IIIa inhibitors and other antiplatelet agents, such as aspirin and clopidogrel, along with HMG-CoA reductase inhibitors.
5. Diabetes mellitus—Although elevated triglycerides, low HDL-C, or both are common in patients with diabetes, clinical trial data support the identification of LDL-C as the primary focus of therapy. Diabetes is designated a CAD risk equivalent in ATP III, and the LDL goal should be below 100 mg/dL.
6. Metabolic syndrome—Factors that characterize the metabolic syndrome are abdominal obesity, dyslipidemia (elevated triglycerides, small dense LDL particles, low HDL-C), raised blood pressure, insulin resistance, and prothrombotic and proinflammatory states. ATP III recognizes this syndrome as a secondary target of risk reduction therapy after the primary target, LDL-C.
Ballantyne CM, Herd A, Ferlic LL et al: Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:736.
Erbel R, Haude M, Hopp HW et al: Coronary artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. N Engl J Med 1998;339:1672.
Pitt B, Waters D, Brown WV et al: Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70.
The Post Coronary Artery Bypass Graft Trial Investigators: The effect of aggressive lowering of low density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein coronary artery bypass grafts. N Engl J Med 1997;336:153.
Stenestrand U, Wallentin L: Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285: 430.
Syvanne M, Nieminen MS, Frick H et al: Association between lipoproteins and the progression of coronary and vein graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:1993.
Walter DH, Schachinger V, Elsner M et al: Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000;85:962.
C. NONPHARMACOLOGIC APPROACHES

1. Dietary modification—The NCEP recommends dietary modification as the first-line treatment for hyperlipidemia (see Table 2–7). It advises a diet that limits cholesterol intake to no more than 200 mg daily and fat intake of less than 30% of total calories, saturated fat constituting less than 7% of daily caloric intake. High intakes of saturated fat, cholesterol, and calories (in excess of body requirements) are implicated as causes for elevated plasma cholesterol. Current recommendations for dietary modification are founded largely on both population-based observational studies and smaller, controlled dietary trials.
Saturated, polyunsaturated, and monounsaturated fats are thought to raise, lower, and have no effect on serum cholesterol, respectively. It has been postulated that monounsaturated fats (eg, olive oil, rapeseed oil), which consist mainly of oleic acid, lower serum cholesterol as much as do polyunsaturated fats, which consist mainly of linoleic acid. The monounsaturated fats offer the added benefit of maintaining heart-protective HDL-C levels. One randomized trial involving postmyocardial infarction patients suggested that intake of n-3 polyunsaturated fatty acids reduced nonfatal myocardial infarction, cerebrovascular accidents, and mortality rates as compared with vitamin E and placebo. However, the study was limited by relatively high drug discontinuation rates. The favorable effects of polyunsaturated fat on serum cholesterol have been counterbalanced by evidence that high intake not only tends to lower HDL levels but may promote gallstone formation.
Trans-fatty acids are formed by commercial hydrogenation processes, which harden polyunsaturate-rich marine and vegetable oils. In the United States, consumption of dietary trans-fatty acids averages about 8–10 g/d, or approximately 6–8% of total daily fat intake, much of it in the form of margarine. Lipid profiles are known to be adversely affected by a high trans-fatty-acid diet, which depresses mean HDL-C levels and elevates mean LDL-C levels. Patients at increased risk of atherosclerosis should therefore limit their intake of this type of fat.
Stearic acid, which contributes substantially to the fatty acid composition in beef and other animal products, has been found to be as effective as oleic acid (monounsaturated fat) in lowering plasma cholesterol, when either one replaced palmitic acid (saturated fat). These findings have implications for the use of lean beef as a meat choice in a lipid-lowering diet.
The ATP III also emphasizes the use of plant stanols and sterols and viscous (soluble) fiber as therapeutic dietary options to enhance the lowering of LDL-C.
Clearly, research remains equivocal on certain key issues: the most effective macronutrient composition of a lipid-lowering diet and the relationship of exogenous cholesterol to serum lipid levels.
DeLorgeril M, Salen P, Martin J-L et al: Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction. Circulation 1999;99:779.
Denke MA: Dietary prescriptions to control dyslipidemias. Circulation 2002;105:132.
GISSI-Prevenzione Investigators: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447.
Von Schacky C, Angerer P, Kothny W et al: The effect of dietary w-3 fatty acids on coronary atherosclerosis: A randomized, double blind, placebo controlled trial. Ann Intern Med 1999;130:554.
2. Exercise—Daily physical activity is recommended as an adjunct to dietary modification for the initial treatment of hyperlipidemia. Cross-sectional and prospective studies have provided evidence suggesting that increased physical activity reduces the risk of morbidity and mortality from CAD. An independent relationship between exercise and fitness, and the level of total-C, HDL, LDL, and triglycerides has yet to be established definitively, however. The effects of exercise on plasma lipids and lipoproteins may be a consequence of changes in body weight, diet, or medication use.
It thus appears that individuals with high total cholesterol, LDL, and triglyceride levels and those with low HDL levels can show favorable changes in these parameters with physical training (both endurance and resistance). A randomized, controlled trial examined dietary modification and aerobic exercise with controls and concluded that the combination of diet and exercise reduced LDL levels but not HDL levels. Moreover, diet or exercise alone did not significantly alter LDL levels. What still needs to be defined, however, is the intensity, duration, and frequency of exercise necessary to benefit patients.
Stampfer MJ, Hu FB, Manson JE et al: Primary prevention of coronary heart disease through diet and lifestyle. N Engl J Med 2000;343:16.
Stefanik ML, Mackey S, Sheehan M et al: Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998;339:12.